This proposal is designed to identify genetic factors which play a crucial role in the maturation phase of spermatogenesis. The investigator proposes to examine the non-pleiotropic mouse mutant, Lvs (lacking vigorous sperm). This transgene-induced mutation appears to affect spermatogenesis at the time of nuclear condensation and displays two unique properties: genetic dominance and a modifying effect of the genetic background. Light and electron microscopy reveals that spermatogenesis proceeds normally until nuclear condensation, which occurs but gives rise to a variety of abnormally shaped nuclei resulting in male sterility. The mutation is unusual in that it is genetically dominant causing the abnormal phenotype even though a normal copy of the chromosomal region is present. The phenotype is fully penetrant on some common inbred backgrounds (SJL and FVB) but totally non-penetrant on others (C57BL/6 and BALB/c) giving a fully fertile phenotype. Data accumulated to date indicate that this epistatic modification of the Lvs phenotype is due to a single locus. The Specific Aims of this small grant RO3 proposal are to generate molecular data (structural analysis and isolation of putative Lvs gene) which will lay the foundations for a more comprehensive RO1 grant aimed at identifying the Lvs gene, studying its biology, mapping of the putative modifier locus and examining the significance of Lvs in human male infertility.